This project is concerned with the physiological and genetic regulation of drug resistance in Mycobacterium tuberculosis H37Ra, Mycobacterium bovis BCG, Mycobacterium avium, Mycobacterium farcinica, Mycobacterium intracell@lare and Mycobacterium kansasii and with genetic relationships among these pathogenic mycobacteria. The antitubercular drugs to be used include cycloserine, ethambutol, ethionamide, isonicotanic hydrazide, kanamycin, pyrazinamide, para-aminosalicylic acid, rifamycin, streptomycin and viomycin. One phase of this project is concerned with developing methods to retard the emergence of drug resistant variants. Another phase of this project consists of a search for episomal or plasmid deoxyribunucleic acid (DNA) in pathogenic mycobacteria and for inactivation of antitubercular drugs by extracts of pathogenic mycobacteria. In addition, nucleotide sequence homology among DNA samples from pathogenic mycobacteria will be assessed and attempts to transfer drug resistance and other genetic markers will be made. These studies should provide information about the emergence and spread of drug resistance in pathogenic mycobacterial populations and provide some data about the possibility that new mycobacterial pathogens are arising by genetic recombination.